The general objectives of this proposal are to gain educational and basic laboratory training in molecular genetic methods and human genetics in general, and apply them to ophthalmologic disorders in order to substantively contribute to the understanding and possible treatment of inherited ocular disorders. These general goals will be specifically met by attending courses and conferences as described at the end of Section 2 and by performing gene linkage studies on North Carolina Macular Dystrophy (NCMD) (previously called dominant progressive foveal dystrophy of Lefler, Wadsworth and Sidbury). This dominantly inherited retinal disorder, which comprises over a 1,400 member kindred, has an infantile onset, complete penetrance and variable expressivity, and affects primarily central vision causing 20/200 visual acuity in severely affected individuals. The fundu- scopic appearance of the milder cases closely resembles the appearance of age-related macular degeneration (AMD). A basic molecular understanding of NCMD may shed light on the more common problem of AMD, the most common cause of legal blindness in the American elderly. Briefly, the techniques employed to perform gene-linkage analysis are now well established. First, the pedigree is ascertained and blood collected from the significant family members, to set up lymphoblasts cell lines which provide a source of DNA for study. Then, using restriction enzymes and cDNA probes the pedigree is examined for polymorphisms. Linkage analysis is then performed in an effort to establish the chromosomal location of the gene for NCMD. Once linkage to a chromosome is found, fine mapping techniques (macro restriction mapping, field inversion gel electrophoresis, detection of Hpall tiny fragment islands, yeast artificial chromosomes, hopping libraries, and subtraction hybridization) will be used. In addition, the identification of a number of highly polymorphic DNA probes tightly linked to NCMD has important clinical implications in genetic counseling and prenatal diagnosis.